The present invention relates to analgesic peptides, and, in particular peptidase-resistant pentapeptides.
Enkephalins are naturally occurring pentapeptides. There are two known enkephalins. Methionine-enkephalins have the amino acid sequence (1): ##STR2## Leucine-enkephalins have the amino acid sequence (2): ##STR3## Both enkephalins have strong analgesic activity. (J. Hughes et al., Nature, 258 577 (1975). However, when naturally occurring enkephalins are administered intravenously, they tend to be digested by endogenous peptidases, hence, intravenously administered enkephalins are of limited medical use. It has been reported that cleavage of the peptide bond between the tyrosine residue at the 1 position and the glycine residue at the 2 position results in the complete loss of analgesic activity. (M. Ueki, Yuki Gosei Kagaku Kyokaishi, Japan, 44 (3), 219 (1986).
Extensive structural modifications of the basic enkephalin compound have been made. While some of these modified compounds have demonstrated enhanced activity, none of the modified compounds involve the use of a trifluoro amino acid in a pentapeptide sequence. Nor, do they suggest trifluoro amino acid containing enkephalin analogs. For example, see P. Hansen and B. Morgan, "Opioid Petpides: Biology, Chemistry and Genetics," The Peptides, Vol. 6, Chapter 8 (1984).
The cleavage of peptidases will be inhibited if the enzymes do not recognize the above-referenced specific amino acid residues in the substrate peptide. Methionine-enkephalins and their hexapeptide, heptapeptide and octapeptide C-terminus extensions, have been prepared and used with pedtidase inhibitors. While some of these compounds have been effective, none of the compounds involve or suggest the use of a trifluoro amino acid in a pentapeptide sequence to inhibit the action of endogenous peptidases. For example, see A. T. McKnight et al., Eur. J. Pharmacol., 86, 393 (1983).
U.S. Pat. No. 4,278,596 to Garsky discloses analgesic pentapeptides of the formula: ##STR4## wherein R.sup.1 is hydrogen, methyl, ethyl, propyl, 2-methyl-2-pentenyl, 2-methyl-1-pentenyl, cyclopropylmethyl, or cyclobutylmethyl; R.sup.2, R.sup.3, and R.sup.4 are, independently, hydrogen or methyl; and wherein X is --OH, --NH.sub.2, --NHC.sub.n H.sub.2n+1 (where n is 1, 2, 3, or 4), --OR.sup.3, or CH.sub.2 OR.sup.3, where R.sup.3 is a hydrogen or lower alkyl of from 1 to 4 carbon atoms; and the pharmaceutically acceptable salts thereof. Garsky does not suggest or disclose trifluoro-enkephalin analogs.
U.S. Pat. No. 4,261,883 to Smolarsky discloses N-aralkyl and N-aralkenyl substituted enkephalinamide analogs having analgesic and opioid properties. The analgesic comprises a short chain polypeptide having at least three members. The short chain polypeptide terminates in an N-substituted carboxy amide. Wherein the substituent is an aryl group of from 0 to 1 site of ethylenic unsaturation (i.e., aralkyl and aralkenyl). The polypeptide chain includes at the carboxy end, going from amine to carboxy, at least a tripeptide group L-tyr-D-ala-gly. Smolarsky does not disclose or suggest trifluoro enkephalin analogs.
Japanese Patent No. J5 6036-441 discloses the production of enkephalin derivatives by reacting a protected enkephalin derivative with trifluoromethane sulphonic acid. In the method of production of the enkephalin derivatives, compounds of formula (I) are reacted with trifluoromethane sulphonic acid (TFMA; a deprotecting agent) and thioether derivatives of formula II. ##STR5## In the above compounds, R.sub.1 is a lower alkyl, R.sub.2 is an aralkyloxycarbonyl or alkoxycarbonyl and R.sub.3 and R.sub.4 are lower alkyls. Japanese Patent J5 6036-441 does not disclose or suggest analgesic trifluoro enhephalin analogs.
European Patent 005658 discloses enkephalin peptide analogs (and their acid addition salts) of the formula: ##STR6## wherein A is Phe or pF-Phe; B is Met, Leu, monofluoro-leu, Pro, monofluoro-Pro or a single bond; Y is a halogen, a 1-4C alkyl mono- or polysubstituted by a halogen or by a phenyl, an amino group --NHX, a sulphonamido group --NHSO.sub.2 X, a carbonyl group --COX or an acylamino group --NHCO(CH.sub.2).sub.m X; X is a halogen, a 1-4C alkyl mono or polysubstituted halogen, a phenyl, or a halo substituted benzhydryl, an alpha or beta naphthyl, or a residue of mono- or polycyclic group chosen from thiophene, quinoline, isoquinoline, acridine and pyridine, wherein m is 0-4 and n is 0-6. The European Patent does not disclose or suggest trifluoro enkephalin analogs.
It is, therefore, an object of the present invention to provide analgesic trifluoro enkephalin analogs.
It is another object of the present invention to provide enkephalin analogues which can effectively be administered intravenously and are peptidase resistant.
It is yet another object of the present invention to provide enkephalin analogues with enhanced analgesic activity.
Other and further objects will become apparent to those skilled in the art upon reading the present specification, and it is not intended in any way to restrict the scope of the invention by setting forth the objects above.